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Yong Yeon Cho - One of the best experts on this subject based on the ideXlab platform.
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abstract 39 fibroblast growth factor induces Neoplastic Cell transformation through a non canonical signaling pathway
Cancer Research, 2015Co-Authors: Sunmi Yoo, Meehyun Lee, Cheoljung Lee, Yong Yeon ChoAbstract:Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Induction of Cell proliferation is closely related with the Cellular signaling pathway activation by stimulation of diverse growth factors such as epidermal growth factor (EGF) and fibroblast growth factor. The stimulation of growth factors induces activation of extraCellular signal-regulated kinases (ERKs)/p90 ribosomal S6 kinases (p90RSK), resulting in induction of Cell proliferation and Cell transformation. Although fibroblast growth factor (FGF) is a well-known growth factor and acts as a ligand of FGF receptor (FGFR), a receptor tyrosine kinase, in cytoplasmic membrane, the tumor promoter potential has not been clearly understood. Here, we provided the evidences that FGF acted as a tumor promoter. We found that FGF-induced Cell proliferation and anchorage-independent Cell transformation were correlated with the induction of G1/S Cell cycle transition. Importantly, we found that kaempferol targeted and inhibited FGFR phosphorylation by in vitro and ex vivo. Interestingly, FGF stimulation utilized a non-canonical signaling pathway to activate RSK2 and ATF-1, which was not transduced by EGF stimulation. We confirmed that kaempferol inhibited tyrosine phosphorylation of FGFR, resulted in nuclear accumulation of phospho-ATF-1 at Ser63. Importantly, kaempferol, PKC412, PD98059 and U0126 inhibited EGF-induced anchorage-independent Cell transformation in JB6 Cl41 Cells. In contrast, FGF-induced Cell transformation in soft agar was not inhibited by PD98059 and U0126. Taken together, these results demonstrate that FGF acts as a tumor promoter and dual inhibition of kaempferol on the kinase activities of FGFR and RSK2 suppresses the FGF-induced Neoplastic Cell transformation through a non-canonical signaling pathway which is not utilized by EGF stimulation. Citation Format: Sun-Mi Yoo, Cheol-Jung Lee, Mee-Hyun Lee, Yong-Yeon Cho. Fibroblast growth factor induces Neoplastic Cell transformation through a non-canonical signaling pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 39. doi:10.1158/1538-7445.AM2015-39
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targeting of magnolin on erks inhibits ras erks rsk2 signaling mediated Neoplastic Cell transformation
Carcinogenesis, 2014Co-Authors: Cheoljung Lee, Zigang Dong, Meehyun Lee, Hye Suk Lee, Hyung Won Ryu, Ji Young Lee, Hyeong Kyu Lee, Yong Yeon ChoAbstract:Mitogen-activated protein kinases play a key role in Cell proliferation, Cell cycle progression and Cell transformation, and activated Ras/extraCellular signal-regulated kinases (ERKs)/ribosomal S6 kinase 2 (RSK2) signaling pathways have been widely identified in many solid tumors. In this study, we found that magnolin, a compound found in the Magnolia species, directly targeted and inhibited ERK1 and ERK2 kinase activities with IC50 values of 87 and 16.5 nM by competing with adenosine triphosphate in an active pocket. Further, we demonstrated that magnolin inhibited epidermal growth factor (EGF)-induced p90RSKs phosphorylation at Thr359/Ser363, but not ERKs phosphorylation at Thr202/Tyr204, and this resulted in inhibition of Cell proliferation by suppression of the G1/S Cell cycle transition. Additionally, p38 kinases, Jun N-terminal kinases and Akts were not involved in the magnolin-mediated inhibitory signaling. Magnolin targeting of ERK1 and 2 activities suppressed the phosphorylation of RSK2 and downstream target proteins including ATF1 and c-Jun and AP-1, a dimer of Jun/Fos, and the transactivation activities of ATF1 and AP-1. Notably, ERKs inhibition by magnolin suppressed EGF-induced anchorage-independent Cell transformation and colony growth of Ras(G12V)-harboring A549 human lung cancer Cells and NIH3T3 Cells stably expressing Ras(G12V) in soft agar. Taken together, these results demonstrated that magnolin might be a naturally occurring chemoprevention and therapeutic agent capable of inhibiting Cell proliferation and transformation by targeting ERK1 and ERK2.
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eriodictyol inhibits rsk2 atf1 signaling and suppresses egf induced Neoplastic Cell transformation
Journal of Biological Chemistry, 2011Co-Authors: Kangdong Liu, Yong Yeon Cho, Ke Yao, Janos Nadas, Dong Joon Kim, Eun Jin Cho, Meehyun Lee, Angelo Pugliese, Jishuai Zhang, Ann M BodeAbstract:RSK2 is a widely expressed serine/threonine kinase, and its activation enhances Cell proliferation. Here, we report that ATF1 is a novel substrate of RSK2 and that RSK2-ATF1 signaling plays an important role in EGF-induced Neoplastic Cell transformation. RSK2 phosphorylated ATF1 at Ser-63 and enhanced ATF1 transcriptional activity. Docking experiments using the crystal structure of the RSK2 N-terminal kinase domain combined with in vitro pulldown assays demonstrated that eriodictyol, a flavanone found in fruits, bound with the N-terminal kinase domain of RSK2 to inhibit RSK2 N-terminal kinase activity. In Cells, eriodictyol inhibited phosphorylation of ATF1 but had no effect on the phosphorylation of RSK, MEK1/2, ERK1/2, p38 or JNKs, indicating that eriodictyol specifically suppresses RSK2 signaling. Furthermore, eriodictyol inhibited RSK2-mediated ATF1 transactivation and tumor promoter-induced transformation of JB6 Cl41 Cells. Eriodictyol or knockdown of RSK2 or ATF1 also suppressed Ras-mediated focus formation. Overall, these results indicate that RSK2-ATF1 signaling plays an important role in Neoplastic Cell transformation and that eriodictyol is a novel natural compound for suppressing RSK2 kinase activity.
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abstract 1227 inhibition of the rsk2 atf1 signaling axis by eriodictyol suppresses Neoplastic Cell transformation
Cancer Research, 2010Co-Authors: Kangdong Liu, Ann M Bode, Ziming Dong, Yong Yeon Cho, Ke Yao, Angelo Pugliese, Duo Zheng, Jishai Zhang, Margarita Malakhova, Zigang DongAbstract:The ribosomal S6 kinase 2 (RSK2), a member of the p90RSK (RSK) family of proteins, is a widely expressed serine/threonine kinase and its activation enhances Cell proliferation. Here we report that activating transcription factor 1(ATF1) is a novel substrate of RSK2 and the RSK2-ATF1 signaling axis plays an important role in Neoplastic Cell transformation. RSK2 phosphorylates ATF1 at Ser63 and enhances the transactivation and transcriptional activities of ATF1. Computational modeling, high-through put screening and in vitro pull down assays demonstrated that eriodictiol, a flavanone found in fruits, binds with the N-terminal kinase domain and linker region of RSK2 and inhibits RSK2 N-terminal kinase activity. In a Cell culture system, eriodictyol treatment suppressed phosphorylation of ATF1, but did not affect phosphorylation of RSK, MEK1/2, ERK1/2, p38 or JNKs, indicating that eriodictyol specifically inhibits RSK2 signaling. Furthermore, eriodictyol inhibited RSK2-mediated ATF1 transactivation activity and Cell transformation induced by tumor promoters in JB6 Cl41 mouse skin epidermal Cells. In a foci formation assay, knockdown of RSK2 or ATF1 suppressed foci formation compared with Ras G12V , Ras G12V /RSK2, Ras G12V /ATF1 and Ras G12V /RSK2/ATF1 expressing Cells. In addition, eriodictyol treatment showed the same effect as RSK2 knockdown in foci formation. Taken together, these results indicated that the RSK2-ATF1 signaling axis plays an important role in Neoplastic Cell transformation and eriodictyol is a new natural compound for selectively inhibiting RSK2 kinase activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1227.
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equol a metabolite of the soybean isoflavone daidzein inhibits Neoplastic Cell transformation by targeting the mek erk p90rsk activator protein 1 pathway
Journal of Biological Chemistry, 2007Co-Authors: Nam Joo Kang, Ki Won Lee, Evgeny A Rogozin, Ann M Bode, Hyong Joo Lee, Yong Yeon Cho, Yongseok Heo, Zigang DongAbstract:Daidzein and genistein are isoflavones found in soybean. Genistein is known to exhibit anticarcinogenic activities and inhibit tyrosine kinase activity. However, the underlying molecular mechanisms of the chemopreventive activities of daidzein and its metabolite, equol, are not understood. Here we report that equol inhibits 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced Neoplastic transformation of JB6 P+ mouse epidermal Cells by targeting the MEK/ERK/p90RSK/activator protein-1 signaling pathway. TPA-induced Neoplastic Cell transformation was inhibited by equol, but not daidzein, at noncytotoxic concentrations in a dose-dependent manner. Equol dose-dependently attenuated TPA-induced activation of activator protein-1 and c-fos, whereas daidzein did not exert any effect when tested at the same concentrations. The TPA-induced phosphorylation of ERK1/2, p90RSK, and Elk, but not MEK or c-Jun N-terminal kinase, was inhibited by equol but not by daidzein. In vitro kinase assays revealed that equol greatly inhibited MEK1, but not Raf1, kinase activity, and an ex vivo kinase assay also demonstrated that equol suppressed TPA-induced MEK1 kinase activity in JB6 P+ Cell lysates. Equol dose-dependently inhibited Neoplastic transformation of JB6 P+ Cells induced by epidermal growth factor or H-Ras. Both in vitro and ex vivo pull-down assays revealed that equol directly bound with glutathione S-transferase-MEK1 to inhibit MEK1 activity without competing with ATP. These results suggested that the antitumor-promoting effect of equol is due to the inhibition of Cell transformation mainly by targeting a MEK signaling pathway. These findings are the first to reveal a molecular basis for the anticancer action of equol and may partially account for the reported chemopreventive effects of soybean.
Zigang Dong - One of the best experts on this subject based on the ideXlab platform.
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targeting of magnolin on erks inhibits ras erks rsk2 signaling mediated Neoplastic Cell transformation
Carcinogenesis, 2014Co-Authors: Cheoljung Lee, Zigang Dong, Meehyun Lee, Hye Suk Lee, Hyung Won Ryu, Ji Young Lee, Hyeong Kyu Lee, Yong Yeon ChoAbstract:Mitogen-activated protein kinases play a key role in Cell proliferation, Cell cycle progression and Cell transformation, and activated Ras/extraCellular signal-regulated kinases (ERKs)/ribosomal S6 kinase 2 (RSK2) signaling pathways have been widely identified in many solid tumors. In this study, we found that magnolin, a compound found in the Magnolia species, directly targeted and inhibited ERK1 and ERK2 kinase activities with IC50 values of 87 and 16.5 nM by competing with adenosine triphosphate in an active pocket. Further, we demonstrated that magnolin inhibited epidermal growth factor (EGF)-induced p90RSKs phosphorylation at Thr359/Ser363, but not ERKs phosphorylation at Thr202/Tyr204, and this resulted in inhibition of Cell proliferation by suppression of the G1/S Cell cycle transition. Additionally, p38 kinases, Jun N-terminal kinases and Akts were not involved in the magnolin-mediated inhibitory signaling. Magnolin targeting of ERK1 and 2 activities suppressed the phosphorylation of RSK2 and downstream target proteins including ATF1 and c-Jun and AP-1, a dimer of Jun/Fos, and the transactivation activities of ATF1 and AP-1. Notably, ERKs inhibition by magnolin suppressed EGF-induced anchorage-independent Cell transformation and colony growth of Ras(G12V)-harboring A549 human lung cancer Cells and NIH3T3 Cells stably expressing Ras(G12V) in soft agar. Taken together, these results demonstrated that magnolin might be a naturally occurring chemoprevention and therapeutic agent capable of inhibiting Cell proliferation and transformation by targeting ERK1 and ERK2.
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abstract 1227 inhibition of the rsk2 atf1 signaling axis by eriodictyol suppresses Neoplastic Cell transformation
Cancer Research, 2010Co-Authors: Kangdong Liu, Ann M Bode, Ziming Dong, Yong Yeon Cho, Ke Yao, Angelo Pugliese, Duo Zheng, Jishai Zhang, Margarita Malakhova, Zigang DongAbstract:The ribosomal S6 kinase 2 (RSK2), a member of the p90RSK (RSK) family of proteins, is a widely expressed serine/threonine kinase and its activation enhances Cell proliferation. Here we report that activating transcription factor 1(ATF1) is a novel substrate of RSK2 and the RSK2-ATF1 signaling axis plays an important role in Neoplastic Cell transformation. RSK2 phosphorylates ATF1 at Ser63 and enhances the transactivation and transcriptional activities of ATF1. Computational modeling, high-through put screening and in vitro pull down assays demonstrated that eriodictiol, a flavanone found in fruits, binds with the N-terminal kinase domain and linker region of RSK2 and inhibits RSK2 N-terminal kinase activity. In a Cell culture system, eriodictyol treatment suppressed phosphorylation of ATF1, but did not affect phosphorylation of RSK, MEK1/2, ERK1/2, p38 or JNKs, indicating that eriodictyol specifically inhibits RSK2 signaling. Furthermore, eriodictyol inhibited RSK2-mediated ATF1 transactivation activity and Cell transformation induced by tumor promoters in JB6 Cl41 mouse skin epidermal Cells. In a foci formation assay, knockdown of RSK2 or ATF1 suppressed foci formation compared with Ras G12V , Ras G12V /RSK2, Ras G12V /ATF1 and Ras G12V /RSK2/ATF1 expressing Cells. In addition, eriodictyol treatment showed the same effect as RSK2 knockdown in foci formation. Taken together, these results indicated that the RSK2-ATF1 signaling axis plays an important role in Neoplastic Cell transformation and eriodictyol is a new natural compound for selectively inhibiting RSK2 kinase activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1227.
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cocoa procyanidins suppress transformation by inhibiting mitogen activated protein kinase kinase
Journal of Biological Chemistry, 2008Co-Authors: Nam Joo Kang, Ki Won Lee, Dong Eun Lee, Evgeny A Rogozin, Ann M Bode, Hyong Joo Lee, Zigang DongAbstract:Cocoa was shown to inhibit chemically induced carcinogenesis in animals and exert antioxidant activity in humans. However, the molecular mechanisms of the chemopreventive potential of cocoa and its active ingredient(s) remain unknown. Here we report that cocoa procyanidins inhibit Neoplastic Cell transformation by suppressing the kinase activity of mitogen-activated protein kinase kinase (MEK). A cocoa procyanidin fraction (CPF) and procyanidin B2 at 5 μg/ml and 40 μm, respectively, inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced Neoplastic transformation of JB6 P+ mouse epidermal (JB6 P+) Cells by 47 and 93%, respectively. The TPA-induced promoter activity and expression of cyclooxygenase-2, which is involved in tumor promotion and inflammation, were dose-dependently inhibited by CPF or procyanidin B2. The activation of activator protein-1 and nuclear factor-κB induced by TPA was also attenuated by CPF or procyanidin B2. The TPA-induced phosphorylation of MEK, extraCellular signal-regulated kinase, and p90 ribosomal s6 kinase was suppressed by CPF or procyanidin B2. In vitro and ex vivo kinase assay data demonstrated that CPF or procyanidin B2 inhibited the kinase activity of MEK1 and directly bound with MEK1. CPF or procyanidin B2 suppressed JB6 P+ Cell transformation induced by epidermal growth factor or H-Ras, both of which are known to be involved in MEK/ERK signal activation. In contrast, theobromine (up to 80 μm) had no effect on TPA-induced transformation, cyclooxygenase-2 expression, the transactivation of activator protein-1 or nuclear factor-κB, or MEK. Notably, procyanidin B2 exerted stronger inhibitory effects compared with PD098059 (a well known pharmacological inhibitor of MEK) on MEK1 activity and Neoplastic Cell transformation.
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equol a metabolite of the soybean isoflavone daidzein inhibits Neoplastic Cell transformation by targeting the mek erk p90rsk activator protein 1 pathway
Journal of Biological Chemistry, 2007Co-Authors: Nam Joo Kang, Ki Won Lee, Evgeny A Rogozin, Ann M Bode, Hyong Joo Lee, Yong Yeon Cho, Yongseok Heo, Zigang DongAbstract:Daidzein and genistein are isoflavones found in soybean. Genistein is known to exhibit anticarcinogenic activities and inhibit tyrosine kinase activity. However, the underlying molecular mechanisms of the chemopreventive activities of daidzein and its metabolite, equol, are not understood. Here we report that equol inhibits 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced Neoplastic transformation of JB6 P+ mouse epidermal Cells by targeting the MEK/ERK/p90RSK/activator protein-1 signaling pathway. TPA-induced Neoplastic Cell transformation was inhibited by equol, but not daidzein, at noncytotoxic concentrations in a dose-dependent manner. Equol dose-dependently attenuated TPA-induced activation of activator protein-1 and c-fos, whereas daidzein did not exert any effect when tested at the same concentrations. The TPA-induced phosphorylation of ERK1/2, p90RSK, and Elk, but not MEK or c-Jun N-terminal kinase, was inhibited by equol but not by daidzein. In vitro kinase assays revealed that equol greatly inhibited MEK1, but not Raf1, kinase activity, and an ex vivo kinase assay also demonstrated that equol suppressed TPA-induced MEK1 kinase activity in JB6 P+ Cell lysates. Equol dose-dependently inhibited Neoplastic transformation of JB6 P+ Cells induced by epidermal growth factor or H-Ras. Both in vitro and ex vivo pull-down assays revealed that equol directly bound with glutathione S-transferase-MEK1 to inhibit MEK1 activity without competing with ATP. These results suggested that the antitumor-promoting effect of equol is due to the inhibition of Cell transformation mainly by targeting a MEK signaling pathway. These findings are the first to reveal a molecular basis for the anticancer action of equol and may partially account for the reported chemopreventive effects of soybean.
Ann M Bode - One of the best experts on this subject based on the ideXlab platform.
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eriodictyol inhibits rsk2 atf1 signaling and suppresses egf induced Neoplastic Cell transformation
Journal of Biological Chemistry, 2011Co-Authors: Kangdong Liu, Yong Yeon Cho, Ke Yao, Janos Nadas, Dong Joon Kim, Eun Jin Cho, Meehyun Lee, Angelo Pugliese, Jishuai Zhang, Ann M BodeAbstract:RSK2 is a widely expressed serine/threonine kinase, and its activation enhances Cell proliferation. Here, we report that ATF1 is a novel substrate of RSK2 and that RSK2-ATF1 signaling plays an important role in EGF-induced Neoplastic Cell transformation. RSK2 phosphorylated ATF1 at Ser-63 and enhanced ATF1 transcriptional activity. Docking experiments using the crystal structure of the RSK2 N-terminal kinase domain combined with in vitro pulldown assays demonstrated that eriodictyol, a flavanone found in fruits, bound with the N-terminal kinase domain of RSK2 to inhibit RSK2 N-terminal kinase activity. In Cells, eriodictyol inhibited phosphorylation of ATF1 but had no effect on the phosphorylation of RSK, MEK1/2, ERK1/2, p38 or JNKs, indicating that eriodictyol specifically suppresses RSK2 signaling. Furthermore, eriodictyol inhibited RSK2-mediated ATF1 transactivation and tumor promoter-induced transformation of JB6 Cl41 Cells. Eriodictyol or knockdown of RSK2 or ATF1 also suppressed Ras-mediated focus formation. Overall, these results indicate that RSK2-ATF1 signaling plays an important role in Neoplastic Cell transformation and that eriodictyol is a novel natural compound for suppressing RSK2 kinase activity.
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abstract 1227 inhibition of the rsk2 atf1 signaling axis by eriodictyol suppresses Neoplastic Cell transformation
Cancer Research, 2010Co-Authors: Kangdong Liu, Ann M Bode, Ziming Dong, Yong Yeon Cho, Ke Yao, Angelo Pugliese, Duo Zheng, Jishai Zhang, Margarita Malakhova, Zigang DongAbstract:The ribosomal S6 kinase 2 (RSK2), a member of the p90RSK (RSK) family of proteins, is a widely expressed serine/threonine kinase and its activation enhances Cell proliferation. Here we report that activating transcription factor 1(ATF1) is a novel substrate of RSK2 and the RSK2-ATF1 signaling axis plays an important role in Neoplastic Cell transformation. RSK2 phosphorylates ATF1 at Ser63 and enhances the transactivation and transcriptional activities of ATF1. Computational modeling, high-through put screening and in vitro pull down assays demonstrated that eriodictiol, a flavanone found in fruits, binds with the N-terminal kinase domain and linker region of RSK2 and inhibits RSK2 N-terminal kinase activity. In a Cell culture system, eriodictyol treatment suppressed phosphorylation of ATF1, but did not affect phosphorylation of RSK, MEK1/2, ERK1/2, p38 or JNKs, indicating that eriodictyol specifically inhibits RSK2 signaling. Furthermore, eriodictyol inhibited RSK2-mediated ATF1 transactivation activity and Cell transformation induced by tumor promoters in JB6 Cl41 mouse skin epidermal Cells. In a foci formation assay, knockdown of RSK2 or ATF1 suppressed foci formation compared with Ras G12V , Ras G12V /RSK2, Ras G12V /ATF1 and Ras G12V /RSK2/ATF1 expressing Cells. In addition, eriodictyol treatment showed the same effect as RSK2 knockdown in foci formation. Taken together, these results indicated that the RSK2-ATF1 signaling axis plays an important role in Neoplastic Cell transformation and eriodictyol is a new natural compound for selectively inhibiting RSK2 kinase activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1227.
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cocoa procyanidins suppress transformation by inhibiting mitogen activated protein kinase kinase
Journal of Biological Chemistry, 2008Co-Authors: Nam Joo Kang, Ki Won Lee, Dong Eun Lee, Evgeny A Rogozin, Ann M Bode, Hyong Joo Lee, Zigang DongAbstract:Cocoa was shown to inhibit chemically induced carcinogenesis in animals and exert antioxidant activity in humans. However, the molecular mechanisms of the chemopreventive potential of cocoa and its active ingredient(s) remain unknown. Here we report that cocoa procyanidins inhibit Neoplastic Cell transformation by suppressing the kinase activity of mitogen-activated protein kinase kinase (MEK). A cocoa procyanidin fraction (CPF) and procyanidin B2 at 5 μg/ml and 40 μm, respectively, inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced Neoplastic transformation of JB6 P+ mouse epidermal (JB6 P+) Cells by 47 and 93%, respectively. The TPA-induced promoter activity and expression of cyclooxygenase-2, which is involved in tumor promotion and inflammation, were dose-dependently inhibited by CPF or procyanidin B2. The activation of activator protein-1 and nuclear factor-κB induced by TPA was also attenuated by CPF or procyanidin B2. The TPA-induced phosphorylation of MEK, extraCellular signal-regulated kinase, and p90 ribosomal s6 kinase was suppressed by CPF or procyanidin B2. In vitro and ex vivo kinase assay data demonstrated that CPF or procyanidin B2 inhibited the kinase activity of MEK1 and directly bound with MEK1. CPF or procyanidin B2 suppressed JB6 P+ Cell transformation induced by epidermal growth factor or H-Ras, both of which are known to be involved in MEK/ERK signal activation. In contrast, theobromine (up to 80 μm) had no effect on TPA-induced transformation, cyclooxygenase-2 expression, the transactivation of activator protein-1 or nuclear factor-κB, or MEK. Notably, procyanidin B2 exerted stronger inhibitory effects compared with PD098059 (a well known pharmacological inhibitor of MEK) on MEK1 activity and Neoplastic Cell transformation.
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equol a metabolite of the soybean isoflavone daidzein inhibits Neoplastic Cell transformation by targeting the mek erk p90rsk activator protein 1 pathway
Journal of Biological Chemistry, 2007Co-Authors: Nam Joo Kang, Ki Won Lee, Evgeny A Rogozin, Ann M Bode, Hyong Joo Lee, Yong Yeon Cho, Yongseok Heo, Zigang DongAbstract:Daidzein and genistein are isoflavones found in soybean. Genistein is known to exhibit anticarcinogenic activities and inhibit tyrosine kinase activity. However, the underlying molecular mechanisms of the chemopreventive activities of daidzein and its metabolite, equol, are not understood. Here we report that equol inhibits 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced Neoplastic transformation of JB6 P+ mouse epidermal Cells by targeting the MEK/ERK/p90RSK/activator protein-1 signaling pathway. TPA-induced Neoplastic Cell transformation was inhibited by equol, but not daidzein, at noncytotoxic concentrations in a dose-dependent manner. Equol dose-dependently attenuated TPA-induced activation of activator protein-1 and c-fos, whereas daidzein did not exert any effect when tested at the same concentrations. The TPA-induced phosphorylation of ERK1/2, p90RSK, and Elk, but not MEK or c-Jun N-terminal kinase, was inhibited by equol but not by daidzein. In vitro kinase assays revealed that equol greatly inhibited MEK1, but not Raf1, kinase activity, and an ex vivo kinase assay also demonstrated that equol suppressed TPA-induced MEK1 kinase activity in JB6 P+ Cell lysates. Equol dose-dependently inhibited Neoplastic transformation of JB6 P+ Cells induced by epidermal growth factor or H-Ras. Both in vitro and ex vivo pull-down assays revealed that equol directly bound with glutathione S-transferase-MEK1 to inhibit MEK1 activity without competing with ATP. These results suggested that the antitumor-promoting effect of equol is due to the inhibition of Cell transformation mainly by targeting a MEK signaling pathway. These findings are the first to reveal a molecular basis for the anticancer action of equol and may partially account for the reported chemopreventive effects of soybean.
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myricetin is a novel natural inhibitor of Neoplastic Cell transformation and mek1
Carcinogenesis, 2007Co-Authors: Nam Joo Kang, Ki Won Lee, Evgeny A Rogozin, Ann M Bode, Hyong Joo Lee, Yong Yeon Cho, Honggyum Kim, Youngjoon SurhAbstract:Evidence suggests that mitogen-activated protein kinase kinase (MEK) plays a role in Cell transformation and tumor development and might be a significant target for chemoprevention. 3,5,4'-Trihydroxy-trans-stilbene (resveratrol), a non-flavonoid polyphenol found in various foods and beverages, including red wines, is reported to be a natural chemopreventive agent. However, the concentrations required to exert these effects might be difficult to achieve by drinking only one or two glasses of red wine a day. On the other hand, the flavonol content of red wine is approximately 30 times higher than that of resveratrol. Here we demonstrated that 3,3',4',5,5',7-hexahydroxyflavone (myricetin), one of the major flavonols in red wine, is a novel inhibitor of MEK1 activity and transformation of JB6 P+ mouse epidermal Cells. Myricetin (10 microM) inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA) or epidermal growth factor (EGF)-induced Cell transformation by 76 or 72%, respectively, compared with respective reductions of 26 or 19% by resveratrol (20 microM). A combination of myricetin and resveratrol exerted additive but not synergistic effects on either TPA- or EGF-induced transformation. Myricetin, but not resveratrol, attenuated tumor promoter-induced activation of c-fos or activator protein-1. Myricetin strongly inhibited MEK1 kinase activity and suppressed TPA- or EGF-induced phosphorylation of extraCellular signal-regulated kinase (ERK) or p90 ribosomal S6 kinase, downstream targets of MEK. Moreover, myricetin inhibited H-Ras-induced Cell transformation more effectively than either PD098059, a MEK inhibitor, or resveratrol. Myricetin directly bound with glutathione S-transferase-MEK1 but did not compete with ATP. Overall, these results indicated that myricetin has potent anticancer-promoting activity and mainly targets MEK signaling, which may contribute to the chemopreventive potential of several foods including red wines.
Rakesh K Jain - One of the best experts on this subject based on the ideXlab platform.
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taxane induced apoptosis decompresses blood vessels and lowers interstitial fluid pressure in solid tumors clinical implications
Cancer Research, 1999Co-Authors: Genevieeve Griffonetienne, Yves Boucher, Christian Brekken, Herman D Suit, Rakesh K JainAbstract:Elevated tumor interstitial fluid pressure (IFP) is partly responsible for the poor penetration and distribution of therapeutic agents in solid tumors. The etiology of tumor interstitial hypertension is poorly understood. We have postulated that the solid stress generated by tumor Cells growing in a confined space compresses blood vessels and increases tumor microvascular pressure and IFP. To test the hypothesis that Neoplastic Cell loss would decompress blood vessels and lower IFP, we induced apoptosis in tumors with paclitaxel and docetaxel. Taxanes inhibited the growth of the murine mammary carcinoma (MCa-IV) and of the human soft tissue sarcoma (HSTS-26T). Taxanes induced apoptosis and reduced the density of intact Neoplastic Cells in both MCa-IV and HSTS-26T. To determine whether Neoplastic Cell loss decompressed blood vessels, we measured the diameter of tumor vessels in HSTS-26T tumors implanted in transparent dorsal skin fold chambers. At 48 and 96 h after paclitaxel, the diameter of tumor vessels was significantly increased. The increase in vascular diameters was associated with reductions in microvascular pressure and IFP. The changes in Neoplastic Cell density and IFP were also correlated. In the human glioblastoma U87, which is resistant to paclitaxel, the IFP and Cellular density were not modified by paclitaxel treatment. Collectively, these results support the hypothesis that solid stress generated by Neoplastic Cell proliferation increases vascular resistance and IFP. The increase in vessel diameter induced by paclitaxel and docetaxel suggests that taxanes could improve tumor response by increasing the vascular surface area for delivery of therapeutic agents.
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taxane induced apoptosis decompresses blood vessels and lowers interstitial fluid pressure in solid tumors clinical implications
Cancer Research, 1999Co-Authors: Genevieeve Griffonetienne, Yves Boucher, Christian Brekken, Herman D Suit, Rakesh K JainAbstract:Elevated tumor interstitial fluid pressure (IFP) is partly responsible for the poor penetration and distribution of therapeutic agents in solid tumors. The etiology of tumor interstitial hypertension is poorly understood. We have postulated that the solid stress generated by tumor Cells growing in a confined space compresses blood vessels and increases tumor microvascular pressure and IFP. To test the hypothesis that Neoplastic Cell loss would decompress blood vessels and lower IFP, we induced apoptosis in tumors with paclitaxel and docetaxel. Taxanes inhibited the growth of the murine mammary carcinoma (MCa-IV) and of the human soft tissue sarcoma (HSTS-26T). Taxanes induced apoptosis and reduced the density of intact Neoplastic Cells in both MCa-IV and HSTS-26T. To determine whether Neoplastic Cell loss decompressed blood vessels, we measured the diameter of tumor vessels in HSTS-26T tumors implanted in transparent dorsal skin fold chambers. At 48 and 96 h after paclitaxel, the diameter of tumor vessels was significantly increased. The increase in vascular diameters was associated with reductions in microvascular pressure and IFP. The changes in Neoplastic Cell density and IFP were also correlated. In the human glioblastoma U87, which is resistant to paclitaxel, the IFP and Cellular density were not modified by paclitaxel treatment. Collectively, these results support the hypothesis that solid stress generated by Neoplastic Cell proliferation increases vascular resistance and IFP. The increase in vessel diameter induced by paclitaxel and docetaxel suggests that taxanes could improve tumor response by increasing the vascular surface area for delivery of therapeutic agents.
Ki Won Lee - One of the best experts on this subject based on the ideXlab platform.
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cocoa procyanidins suppress transformation by inhibiting mitogen activated protein kinase kinase
Journal of Biological Chemistry, 2008Co-Authors: Nam Joo Kang, Ki Won Lee, Dong Eun Lee, Evgeny A Rogozin, Ann M Bode, Hyong Joo Lee, Zigang DongAbstract:Cocoa was shown to inhibit chemically induced carcinogenesis in animals and exert antioxidant activity in humans. However, the molecular mechanisms of the chemopreventive potential of cocoa and its active ingredient(s) remain unknown. Here we report that cocoa procyanidins inhibit Neoplastic Cell transformation by suppressing the kinase activity of mitogen-activated protein kinase kinase (MEK). A cocoa procyanidin fraction (CPF) and procyanidin B2 at 5 μg/ml and 40 μm, respectively, inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced Neoplastic transformation of JB6 P+ mouse epidermal (JB6 P+) Cells by 47 and 93%, respectively. The TPA-induced promoter activity and expression of cyclooxygenase-2, which is involved in tumor promotion and inflammation, were dose-dependently inhibited by CPF or procyanidin B2. The activation of activator protein-1 and nuclear factor-κB induced by TPA was also attenuated by CPF or procyanidin B2. The TPA-induced phosphorylation of MEK, extraCellular signal-regulated kinase, and p90 ribosomal s6 kinase was suppressed by CPF or procyanidin B2. In vitro and ex vivo kinase assay data demonstrated that CPF or procyanidin B2 inhibited the kinase activity of MEK1 and directly bound with MEK1. CPF or procyanidin B2 suppressed JB6 P+ Cell transformation induced by epidermal growth factor or H-Ras, both of which are known to be involved in MEK/ERK signal activation. In contrast, theobromine (up to 80 μm) had no effect on TPA-induced transformation, cyclooxygenase-2 expression, the transactivation of activator protein-1 or nuclear factor-κB, or MEK. Notably, procyanidin B2 exerted stronger inhibitory effects compared with PD098059 (a well known pharmacological inhibitor of MEK) on MEK1 activity and Neoplastic Cell transformation.
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equol a metabolite of the soybean isoflavone daidzein inhibits Neoplastic Cell transformation by targeting the mek erk p90rsk activator protein 1 pathway
Journal of Biological Chemistry, 2007Co-Authors: Nam Joo Kang, Ki Won Lee, Evgeny A Rogozin, Ann M Bode, Hyong Joo Lee, Yong Yeon Cho, Yongseok Heo, Zigang DongAbstract:Daidzein and genistein are isoflavones found in soybean. Genistein is known to exhibit anticarcinogenic activities and inhibit tyrosine kinase activity. However, the underlying molecular mechanisms of the chemopreventive activities of daidzein and its metabolite, equol, are not understood. Here we report that equol inhibits 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced Neoplastic transformation of JB6 P+ mouse epidermal Cells by targeting the MEK/ERK/p90RSK/activator protein-1 signaling pathway. TPA-induced Neoplastic Cell transformation was inhibited by equol, but not daidzein, at noncytotoxic concentrations in a dose-dependent manner. Equol dose-dependently attenuated TPA-induced activation of activator protein-1 and c-fos, whereas daidzein did not exert any effect when tested at the same concentrations. The TPA-induced phosphorylation of ERK1/2, p90RSK, and Elk, but not MEK or c-Jun N-terminal kinase, was inhibited by equol but not by daidzein. In vitro kinase assays revealed that equol greatly inhibited MEK1, but not Raf1, kinase activity, and an ex vivo kinase assay also demonstrated that equol suppressed TPA-induced MEK1 kinase activity in JB6 P+ Cell lysates. Equol dose-dependently inhibited Neoplastic transformation of JB6 P+ Cells induced by epidermal growth factor or H-Ras. Both in vitro and ex vivo pull-down assays revealed that equol directly bound with glutathione S-transferase-MEK1 to inhibit MEK1 activity without competing with ATP. These results suggested that the antitumor-promoting effect of equol is due to the inhibition of Cell transformation mainly by targeting a MEK signaling pathway. These findings are the first to reveal a molecular basis for the anticancer action of equol and may partially account for the reported chemopreventive effects of soybean.
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myricetin is a novel natural inhibitor of Neoplastic Cell transformation and mek1
Carcinogenesis, 2007Co-Authors: Nam Joo Kang, Ki Won Lee, Evgeny A Rogozin, Ann M Bode, Hyong Joo Lee, Yong Yeon Cho, Honggyum Kim, Youngjoon SurhAbstract:Evidence suggests that mitogen-activated protein kinase kinase (MEK) plays a role in Cell transformation and tumor development and might be a significant target for chemoprevention. 3,5,4'-Trihydroxy-trans-stilbene (resveratrol), a non-flavonoid polyphenol found in various foods and beverages, including red wines, is reported to be a natural chemopreventive agent. However, the concentrations required to exert these effects might be difficult to achieve by drinking only one or two glasses of red wine a day. On the other hand, the flavonol content of red wine is approximately 30 times higher than that of resveratrol. Here we demonstrated that 3,3',4',5,5',7-hexahydroxyflavone (myricetin), one of the major flavonols in red wine, is a novel inhibitor of MEK1 activity and transformation of JB6 P+ mouse epidermal Cells. Myricetin (10 microM) inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA) or epidermal growth factor (EGF)-induced Cell transformation by 76 or 72%, respectively, compared with respective reductions of 26 or 19% by resveratrol (20 microM). A combination of myricetin and resveratrol exerted additive but not synergistic effects on either TPA- or EGF-induced transformation. Myricetin, but not resveratrol, attenuated tumor promoter-induced activation of c-fos or activator protein-1. Myricetin strongly inhibited MEK1 kinase activity and suppressed TPA- or EGF-induced phosphorylation of extraCellular signal-regulated kinase (ERK) or p90 ribosomal S6 kinase, downstream targets of MEK. Moreover, myricetin inhibited H-Ras-induced Cell transformation more effectively than either PD098059, a MEK inhibitor, or resveratrol. Myricetin directly bound with glutathione S-transferase-MEK1 but did not compete with ATP. Overall, these results indicated that myricetin has potent anticancer-promoting activity and mainly targets MEK signaling, which may contribute to the chemopreventive potential of several foods including red wines.
